CAMEO
VESICULAR GRAFT-VERSUS-HOST DISEASE CRAIG S. SCHAUDER, M.D., SHARON R. HYMES, M.D., RONALD P. RAPINI, M.D., AND THEODORE F. ZIPF, M.D., PH.D.
A 14-year-old boy with chronic myelogenous leukemia underwent an allogeneic bone marrow transplant after failing conventional therapy. Despite a prophylactic regimen including methotrexate and cyclosporine, he developed acute graft-versus-host disease (GVHD) of the skin, liver, and gastrointestinal tract beginning on day 11 post-transplant. The cutaneous eruption was characterized by macular erythema with progressive desquamation of the trunk, ears, palms, and soles. A biopsy was consistent with grade II GVHD. The multisystem GVHD gradually resolved with prednisone and antithymocyte globulin. Corticosteroid taper subsequently provoked a biopsy proven flare of cutaneous and gastrointestinal GVHD on day 97, which resolved with increased doses of prednisone and the introduction of cyclosporine. On day 240, the cyclosporine was discontinued because of nephrotoxicity, and the prednisone was tapered to alternate day administration. One year after bone marrow transplantation, he developed an extensive vesicular and lichenoid eruption involving the oral mucosa, trunk, distal extremities, palms, and soles. The lichenoid lesions on the extremities, palms, and soles were studded with clear vesicles (Figs. 1 and 2). Concomitantly, transaminase elevation and a liver biopsy confirmed the presence of chronic hepatic GVHD.
Figure 2.
Vesicles on the sole.
Biopsy of a vesicular lesion demonstrated necrotic keratinocytes, exocytosis of lymphocytes, basal layer liquefaction with a subepidermal cleft, and an upper dermal band-like lymphocytic infiltrate consistent with chronic graft-versushost disease (Fig. 3). Herpetic cytopathic changes were not observed. Multiple cutaneous viral, fungal, and bacterial cultures were negative, as were oropharyngeal cultures. The skin lesions gradually cleared, and the liver function tests normalized after hospitalization and treatment with intravenous methylprednisolone and azathioprine. Over the ensuing 10 months, slow taper of the prednisone and azathioprine have been impeded by hepatic GVHD flares. Poikilodermatous and early sclerodermatous changes are currently present at previous sites of cutaneous GVHD, and an occasional lichenoid papule is seen.
DISCUSSION
Chronic graft-versus-host disease (GVHD) is a complex multisystem disease occurring more than 100 days after bone marrow transplantation. Lichenoid and sclerodermoid skin lesions are well described and readily recognized. We recently had the opportunity to participate in the evaluation and treatment of a previously unreported vesicular variant of lichenoid GVHD. Because the appearance of vesicles in an immunosuppressed transplant recipient often heralds disseminated herpes virus infection, we feel that recognition of this form of cutaneous GVHD is especially important. In all immunosuppressed patients, a vesicular eruption warrants a search for herpes virus infection. In
Figure 1. Vesicles on the palm.
From the Departments of Dermatology and Pediatrics, University of Texas Medical School at Houston, and the University of Texas M.D. Anderson Cancer Center, Houston, Texas. Address for correspondence: Sharon R. Hymes, M.D., Department of Dermatology, The University of Texas Medical School at Houston, 6431 Fannin, Suite t.2O4, Houston, TX 77030. 509
International joLirnal of Dermatology Vol. ^\, N o . 7, July 1992
the lesion margins are often indistinct and become confluent as the process generalizes. The prominent palmar/plantar involvement, as demonstrated by our patient, is rarely seen in lichen pianus. Histoiogically, the inflammatory infiltrate is relatively sparse, not always band-like, and necrotic keratinocytes may be located throughout the epidermis. The predominant pathogenetic event in lichen planus is felt to be immune-mediated destruction of the basal cell layer occurring in immunocompetent individuals.' It has been suggested that the primary event is a delayed hypersensitivity reaction in which an unidentified antigen, often being processed in the Langerhans' cells, attracts T-lymphocytes, which in turn destroy keratinocytes."• When extensive cytolysis of basal keratinocytes occurs, a blister cavity forms below the stratum spinosum leading to vesicular lesions of lichen planus.' The precise pathogenesis of lichenoid GVHD is not known. Chronic GVHD is a model of immune, dysregulation in which delayed type hypersensitivity is just one of many impaired T-cell functions. Thymic damage with subsequent alterations in T-cell maturation and balance, as well as infections and environmental factors, all contribute to this autoaggressive phenomenon.''
Figure 3. Liquefaction degeneration, spongiosis, necrotic keratinocytes, lymphocytic infiltrate, and subepidermal vesicle, (hematoxylin and eosin, original magnification x 300) this case, there was no histologic or viral evidence to support this diagnosis. Another diagnosis considered in our patient was a vesicular lichenoid drug eruption, but the clinical pattern of a violaceous lichenoid eruption with prominent palmar/plantar involvement, biopsy-proven hepatic GVHD, response to systemic steroids and azathioprine, as well as the chronic course, support the diagnosis of chronic GVHD. This vesicular pattern has not, to our knowledge, been reported, but is not surprising since lichenoid chronic cutaneous GVHD has striking clinical and histologic similarities to lichen planus. Histoiogically, separation of the basal layer from the dermal papillae, similar to the Max-Joseph clefts seen in severe lichen planus, have been seen in early lichenoid GVHD;' however, vesicular or bullous changes are generally not seen clinically in chronic lichenoid GVHD. Subepidermal bullous lesions may occur in grade 3 or 4 acute GVHD when the entire epidermis becomes necrotic. Bullous changes have also been reported in sclerodermoid chronic GVHD;^ however, these changes are associated with dermal sclerosis, minimal inflammation, and dermal edema. Clinically, the cutaneous eruption of lichenoid chronic GVHD may differ somewhat from lichen planus in its morphology and distribution. In lichenoid GVHD,
REFERENCES
1.
2.
3. 4.
5.
6.
Shulman HM, Sullivan KM, Weiden PL, et nl. Chronic graft-versus-host syndrome in man. Am J Med 1980; 69:204-217. Hymes SR, Farmer ER, Burns WH, et al. Bullous sclerodermalike changes in chronic graft-vs-host disease. Arch Dermatol 1985; 121:1189-1192. Buechner SA. T-cell subsets and macrophages in lichen planus. Dermatologica 1984; 169:325-329. Ragaz A, Ackerman AB. Evolution, maturation, and regression of lesions of lichen planus. Am J Dermatopathol 1981; 3:5-25. Ebner H, Erlach E, Gebhart W. Untersuchungen iiber die Blasenbildung beim lichen ruber planus. Arch Dermatol Forsch 1973; 247:193-205. Hymes SR, Hood AF, Farmer ER. Graft-versus-host disease. In: Jordon RE, ed. Immunologic diseases of the skin. Norwalk, Connecticut: Appleton &i Lange, 1991; 509.
BALSAM COPAIBA DOSE.—One-half (K) to one teaspoonful three times a day.
MEYER DRUG STORE DRS. A. I. & L. E. MEYER, Props. THIBODAUX. LOUISIANA
From the collection of "La Pharmacie Frangaise," New Orleans, Louisiana, Mr. Ben Bavly, Curator. 510
VESICULAR GRAFT-VERSUS-HOST DISEASE CRAIG S. SCHAUDER, M.D., SHARON R. HYMES, M.D., RONALD P. RAPINI, M.D., AND THEODORE F. ZIPF, M.D., PH.D.
A 14-year-old boy with chronic myelogenous leukemia underwent an allogeneic bone marrow transplant after failing conventional therapy. Despite a prophylactic regimen including methotrexate and cyclosporine, he developed acute graft-versus-host disease (GVHD) of the skin, liver, and gastrointestinal tract beginning on day 11 post-transplant. The cutaneous eruption was characterized by macular erythema with progressive desquamation of the trunk, ears, palms, and soles. A biopsy was consistent with grade II GVHD. The multisystem GVHD gradually resolved with prednisone and antithymocyte globulin. Corticosteroid taper subsequently provoked a biopsy proven flare of cutaneous and gastrointestinal GVHD on day 97, which resolved with increased doses of prednisone and the introduction of cyclosporine. On day 240, the cyclosporine was discontinued because of nephrotoxicity, and the prednisone was tapered to alternate day administration. One year after bone marrow transplantation, he developed an extensive vesicular and lichenoid eruption involving the oral mucosa, trunk, distal extremities, palms, and soles. The lichenoid lesions on the extremities, palms, and soles were studded with clear vesicles (Figs. 1 and 2). Concomitantly, transaminase elevation and a liver biopsy confirmed the presence of chronic hepatic GVHD.
Figure 2.
Vesicles on the sole.
Biopsy of a vesicular lesion demonstrated necrotic keratinocytes, exocytosis of lymphocytes, basal layer liquefaction with a subepidermal cleft, and an upper dermal band-like lymphocytic infiltrate consistent with chronic graft-versushost disease (Fig. 3). Herpetic cytopathic changes were not observed. Multiple cutaneous viral, fungal, and bacterial cultures were negative, as were oropharyngeal cultures. The skin lesions gradually cleared, and the liver function tests normalized after hospitalization and treatment with intravenous methylprednisolone and azathioprine. Over the ensuing 10 months, slow taper of the prednisone and azathioprine have been impeded by hepatic GVHD flares. Poikilodermatous and early sclerodermatous changes are currently present at previous sites of cutaneous GVHD, and an occasional lichenoid papule is seen.
DISCUSSION
Chronic graft-versus-host disease (GVHD) is a complex multisystem disease occurring more than 100 days after bone marrow transplantation. Lichenoid and sclerodermoid skin lesions are well described and readily recognized. We recently had the opportunity to participate in the evaluation and treatment of a previously unreported vesicular variant of lichenoid GVHD. Because the appearance of vesicles in an immunosuppressed transplant recipient often heralds disseminated herpes virus infection, we feel that recognition of this form of cutaneous GVHD is especially important. In all immunosuppressed patients, a vesicular eruption warrants a search for herpes virus infection. In
Figure 1. Vesicles on the palm.
From the Departments of Dermatology and Pediatrics, University of Texas Medical School at Houston, and the University of Texas M.D. Anderson Cancer Center, Houston, Texas. Address for correspondence: Sharon R. Hymes, M.D., Department of Dermatology, The University of Texas Medical School at Houston, 6431 Fannin, Suite t.2O4, Houston, TX 77030. 509
International joLirnal of Dermatology Vol. ^\, N o . 7, July 1992
the lesion margins are often indistinct and become confluent as the process generalizes. The prominent palmar/plantar involvement, as demonstrated by our patient, is rarely seen in lichen pianus. Histoiogically, the inflammatory infiltrate is relatively sparse, not always band-like, and necrotic keratinocytes may be located throughout the epidermis. The predominant pathogenetic event in lichen planus is felt to be immune-mediated destruction of the basal cell layer occurring in immunocompetent individuals.' It has been suggested that the primary event is a delayed hypersensitivity reaction in which an unidentified antigen, often being processed in the Langerhans' cells, attracts T-lymphocytes, which in turn destroy keratinocytes."• When extensive cytolysis of basal keratinocytes occurs, a blister cavity forms below the stratum spinosum leading to vesicular lesions of lichen planus.' The precise pathogenesis of lichenoid GVHD is not known. Chronic GVHD is a model of immune, dysregulation in which delayed type hypersensitivity is just one of many impaired T-cell functions. Thymic damage with subsequent alterations in T-cell maturation and balance, as well as infections and environmental factors, all contribute to this autoaggressive phenomenon.''
Figure 3. Liquefaction degeneration, spongiosis, necrotic keratinocytes, lymphocytic infiltrate, and subepidermal vesicle, (hematoxylin and eosin, original magnification x 300) this case, there was no histologic or viral evidence to support this diagnosis. Another diagnosis considered in our patient was a vesicular lichenoid drug eruption, but the clinical pattern of a violaceous lichenoid eruption with prominent palmar/plantar involvement, biopsy-proven hepatic GVHD, response to systemic steroids and azathioprine, as well as the chronic course, support the diagnosis of chronic GVHD. This vesicular pattern has not, to our knowledge, been reported, but is not surprising since lichenoid chronic cutaneous GVHD has striking clinical and histologic similarities to lichen planus. Histoiogically, separation of the basal layer from the dermal papillae, similar to the Max-Joseph clefts seen in severe lichen planus, have been seen in early lichenoid GVHD;' however, vesicular or bullous changes are generally not seen clinically in chronic lichenoid GVHD. Subepidermal bullous lesions may occur in grade 3 or 4 acute GVHD when the entire epidermis becomes necrotic. Bullous changes have also been reported in sclerodermoid chronic GVHD;^ however, these changes are associated with dermal sclerosis, minimal inflammation, and dermal edema. Clinically, the cutaneous eruption of lichenoid chronic GVHD may differ somewhat from lichen planus in its morphology and distribution. In lichenoid GVHD,
REFERENCES
1.
2.
3. 4.
5.
6.
Shulman HM, Sullivan KM, Weiden PL, et nl. Chronic graft-versus-host syndrome in man. Am J Med 1980; 69:204-217. Hymes SR, Farmer ER, Burns WH, et al. Bullous sclerodermalike changes in chronic graft-vs-host disease. Arch Dermatol 1985; 121:1189-1192. Buechner SA. T-cell subsets and macrophages in lichen planus. Dermatologica 1984; 169:325-329. Ragaz A, Ackerman AB. Evolution, maturation, and regression of lesions of lichen planus. Am J Dermatopathol 1981; 3:5-25. Ebner H, Erlach E, Gebhart W. Untersuchungen iiber die Blasenbildung beim lichen ruber planus. Arch Dermatol Forsch 1973; 247:193-205. Hymes SR, Hood AF, Farmer ER. Graft-versus-host disease. In: Jordon RE, ed. Immunologic diseases of the skin. Norwalk, Connecticut: Appleton &i Lange, 1991; 509.
BALSAM COPAIBA DOSE.—One-half (K) to one teaspoonful three times a day.
MEYER DRUG STORE DRS. A. I. & L. E. MEYER, Props. THIBODAUX. LOUISIANA
From the collection of "La Pharmacie Frangaise," New Orleans, Louisiana, Mr. Ben Bavly, Curator. 510
